The rat with transplantable Walker 256 carcinoma (T) with decreased serum T4 and T3 but normalserum TSH and liver alpha-glycerophosphate dehydrogenase (alpha-GPD) activity will be studied further as a model for patients with nonthyroidal disease with decreased serum T3. We intend to determine whether the described decrease in nuclear T3 receptors reflects a specific or general change in nonhistone protein synthesis, whether other aspects of protein synthesis are altered in T rats, and whether pituitary nuclear T3 receptors and growth hormone (GH) content are changed in these animals. We have recently defined the T3 dose response curves for liver alpha-GPD, malic enzyme (ME), and pituitary GH to develop an in vitro model where tumor products may reproduce in cultured cells the effects observed in intact animal-bearing tumors. In this in vitro system, we hope to define the chemical nature of tumor products that affect nuclear T3 receptor and thyroid hormone action. Initial studies suggest 5,5'-diphenylhydantoin (DPH) inhibits TSH secretion, decreases specific nuclear binding of T3, and increases hepatic ME and pituitary GH. We now intend to determine the dose-response relationship between T3 and pituitary TSH and GH secretion in intact rats and cultured anterior pituitary cells. We will also define whether DPH effects on hormone secretion require protein and RNA synthesis. We will further determine whether the drug interacts directly with T3 at the nuclear T3 receptor. The inhibition of T3-induced changes in ME and GH is of particular interest, and this will be characterized by characterizing their appropriate dose-response curves. We will determine whether the above changes reflect new protein synthesis resulting from altered gene transcription. If so, we will determine whether DPH or analogues to be developed may be useful in the management of thyrotoxicosis. (C)